The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index; 35 of the 60 sources its claims cite were checked for support.
Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation
Open accessAbstract
Background The involvement of epigenetic mechanisms in intergenerational transmission of stress effects has been demonstrated in animals but not in humans. Methods Cytosine methylation within the gene encoding for FK506 binding protein 5 (FKBP5) was measured in Holocaust survivors (n = 32), their adult offspring (n = 22), and demographically comparable parent (n = 8) and offspring (n = 9) control subjects, respectively. Cytosine-phosphate-guanine sites for analysis were chosen based on their spatial proximity to the intron 7 glucocorticoid response elements. Results Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring. These effects were observed at bin 3/site 6. Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower. Methylation levels for exposed parents and their offspring were significantly correlated. In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity. The findings suggest the possibility of site specificity to environmental influences, as sites in bins 3 and 2 were differentially associated with parental trauma and the offspring's own childhood trauma, respectively. FKBP5…
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35 of 60 cited sources checked · 21 supported · 1 flagged · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Furthermore, both bins within intron 7 appear to be equally sensitive to glucocorticoid-dependent FKBP5 demethylation in a multipotent human hippocampal progenitor cell line (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Disputedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci sourceExperimental — accuracy not yet measured
The Results report dexamethasone-induced demethylation in intron 7 of human hippocampal progenitor cells, but say the bin affected by early trauma showed the strongest demethylation—not that the bins were equally sensitive. The Methods also describe three CpG bins in intron 7, rather than two. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“Second, reporter gene assays established that methylation of the sites affected FKBP5 gene expression (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results section reports that a methylated FKBP5 intron 7 reporter construct had significantly lower dexamethasone-induced activity than an unmethylated construct. The effect was specific to glucocorticoid stimulation; methylation did not affect baseline activity. Page numbers are not available in our copy. (LLM, conf=0.91)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“After extensive investigation of all relevant regions in the FKBP5 gene that had GR-binding signals including the promoter regions and introns 2, 5, and 7 (31,39), Klengel et al. (38) demonstrated that only intron 7 CpG sites were differentially methylated in response to early abuse in the presence of FKBP5 rs1360780 risk allele.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results report a significant childhood-abuse × rs1360780 genotype interaction on methylation in intron 7 bin 2, but not in the other tested CpG bins. The effect was a decrease in methylation among abuse-exposed risk-allele carriers; the finding concerns this specific bin, not every CpG in intron 7. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“since FKBP5 site-specific demethylation occurs with age (49).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Supportedcites [49] Blair, 2013, Accelerated neurodegeneration through chaperone-mediated oligomerization of tau, J Clin Invest source
Figure 7 (p. 8) reports significant age-related demethylation at specific FKBP5 CpG sites in intron 7 and the promoter. The research article text (p. 9) likewise reports decreased methylation with aging at seven sites in those regions. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Third, using a multipotent human hippocampal progenitor cell line, four of these sites (3 to 6) were shown to be demethylated by glucocorticoid administration (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Partly supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci sourceExperimental — accuracy not yet measured
The Results report that dexamethasone caused significant demethylation of FKBP5 intron 7 CpGs in a multipotent human hippocampal progenitor cell line. They identify three CpGs in the most strongly affected bin, but do not establish that four sites numbered 3–6 were demethylated. (LLM, conf=0.84)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“First, an experiment using chromatin conformation capture revealed that intron 7 is in direct physical contact with the FKBP5 transcriptional start site (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results report that chromatin conformation capture found an interaction between FKBP5 intron 7 and the transcription start site through three-dimensional loop formation. The Methods describe the chromatin conformation capture experiment used to assess that interaction. (LLM, conf=0.94)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Klengel et al. (38) and other investigators (51,52) focusing on early childhood trauma effects and the influence of the gene 3 early life environment interactions on methylation did not assess the contribution of parental experiences, particularly trauma exposure.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Methods (Psychometric instruments; page unavailable) describe measures of participants’ own childhood and lifetime trauma. The Methods analysis of FKBP5 methylation includes participants’ trauma exposure and genotype, but no parental experiences or parental trauma exposure. This supports the claim as it applies to Klengel et al.; the other cited investigators are outside this verdict. (LLM, conf=0.87)
- Partly supportedcites [51] Turecki, 2016, Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review, Biol Psychiatry sourceExperimental — accuracy not yet measured
The Conclusion describes Klengel et al.’s finding on childhood maltreatment, FKBP5 genotype and methylation. The Results discuss parental stress in a separate group of studies, but do not establish that Klengel et al. or the other investigators named in the citing sentence failed to assess parental trauma exposure. (LLM, conf=0.78)
- Partly supportedcites [52] Daskalakis, 2014, Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic review of contributing factors, Front Neurosci sourceExperimental — accuracy not yet measured
The sections on GR-1F promoter site-specific methylation and possible transgenerational effects distinguish studies of childhood adversity from work assessing parental trauma or PTSD, and note that the two influences are difficult to disentangle (page unavailable). The review does not establish that Klengel et al. or all the other investigators cited failed to assess parental experiences, so that categorical part is unsupported. (LLM, conf=0.73)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These results partially replicate previous findings (38) in which bin 2 demethylation was associated with physical and sexual abuse, the FKBP5 risk allele, and their interaction in two separate large cohorts.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Partly supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci sourceExperimental — accuracy not yet measured
The Results (page unavailable) report that intron 7 bin 2 methylation was associated with childhood abuse, FKBP5 risk genotype, and their interaction in the first cohort. In the second cohort, methylation correlated with physical abuse among risk-genotype carriers, but not with sexual abuse. The claim therefore overstates the findings across both cohorts; the methylation analyses involved 76 and 56 participants, respectively, rather than two large samples. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“alterations in methylation at bins 1, 2, and 3 affect GR-induced FKBP5 gene transcription as shown by reporter-gene assay (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Partly supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci sourceExperimental — accuracy not yet measured
The Results ('Functional effects of intron 7 demethylation'; page unavailable) report that methylating an intron 7 reporter construct reduced its dexamethasone-induced activity. The Methods identify bins 1, 2, and 3 in that region, but the assay methylated the construct as a whole; it did not show that alterations in each bin individually affect transcription. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Lower methylation leading to higher FKBP5 messenger RNA and protein levels has been linked to decreased GR sensitivity (38)”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Partly supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci sourceExperimental — accuracy not yet measured
The Results (page not available in our copy) link lower intron 7 methylation to greater glucocorticoid-induced FKBP5 expression and increased glucocorticoid receptor resistance. They do not establish that lower methylation raises FKBP5 protein levels, and report no association with baseline FKBP5 expression. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
- Probably not a substantial claim. 18
- It may state two separate claims as one. 20
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Enduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes (10)(11)(12)(13), in utero effects (14), variations in early postnatal care (15,16), and/or other early life experiences (17) that are influenced by parental exposure (18).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Abstract
What the sources say
- Supportedcites [10] Dias, 2014, Parental olfactory experience influences behavior and neural structure in subsequent generations, Nat Neurosci source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [11] Zaidan, 2013, Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring, Biol Psychiatry source
- Supportedcites [12] Franklin, 2010, Epigenetic transmission of the impact of early stress across generations, Biol Psychiatry source
Citation 18 is attached to the claim that parental exposure influences outcomes in offspring, not to the separately cited list of mediating mechanisms. The Abstract reports that early stress in male mice was followed by behavioral alterations and DNA-methylation changes in their offspring; the Results say those offspring were raised under normal conditions. (LLM, conf=0.88)
- Supportedcites [13] Rodgers, 2013, Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation, J Neurosci source
The citation is attached to the point that parental exposure can influence offspring outcomes. The Introduction (page unavailable) says parental environmental exposures can shape offspring neurodevelopment and identifies changes in the intrauterine environment, lactation, and maternal behavior as relevant pathways. The paper does not need to establish every separately cited mechanism in the sentence to support this point. (LLM, conf=0.86)
- Supportedcites [14] Boersma, 2014, Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats, Epigenetics source
Citation (14) is attached to the in utero effects, not to the separately cited gamete or postnatal-care pathways. The Experimental set-up and Abstract report gestational stress exposure followed by altered Bdnf expression and DNA methylation in adult rat offspring; the Introduction also describes lasting behavioral effects of prenatal stress. The paper does not itself measure offspring behavior, but it reports that evidence as background. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [15] Champagne, 2006, Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring, Endocrinology source
- Not checked — no full text of the sourcecites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Differential methylation of the glucocorticoid receptor (GR) gene associated with maternal behavior has been observed in F1 in rodents at Nr3c1 exon 1 7 promoter (16) and in human offspring with parental PTSD at the ortholog NR3C1 exon 1 F promoter (24).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Abstract
What the sources say
- Not checked — no full text of the sourcecites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
- Supportedcites [24] Yehuda, 2014, Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring, Am J Psychiatry source
The citation is attached to the human-offspring portion of the sentence. The Results (Maternal PTSD, Paternal PTSD and GR-1F promoter methylation) report differences in NR3C1 exon 1F promoter methylation associated with parental PTSD in offspring of Holocaust survivors; the Introduction identifies this human promoter as orthologous to the rat promoter. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Animal models have demonstrated that stress exposure can result in epigenetic alterations in the next generation, and such mechanisms have been hypothesized to underpin vulnerability to symptoms in offspring of trauma survivors (6)(7)(8)(9).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Abstract
What the sources say
- Not checked — no full text of the sourcecites [6] Gapp, 2014, Early life epigenetic programming and transmission of stress-induced traits in mammals: How and when can environmental factors influence traits and their transgenerational inheritance?, Bioessays source
- Partly supportedcites [7] Yehuda, 2009, The relevance of epigenetics to PTSD: Implications for the DSM-V, J Trauma Stress sourceExperimental — accuracy not yet measured
The section “Cytosine Methylation in Response to Variations in Maternal Care: A Behavioral Model” (page unavailable) reports altered DNA methylation in rat pups receiving different levels of maternal care and says associated biological effects were transmitted to a third generation. It does not clearly demonstrate that stress exposure in one generation caused epigenetic alterations in the next; the animal model described is one of variation in maternal care. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [8] Bale, 2015, Epigenetic and transgenerational reprogramming of brain development, Nat Rev Neurosci source
- Not checked — no full text of the sourcecites [9] Dias, 2015, Epigenetic mechanisms underlying learning and the inheritance of learned behaviors, Trends Neurosci source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
Every source the paper cites for this claim was checked and supports it.
In the paper
“For example, lower 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) activity was observed in Holocaust survivors compared with control subjects, presumably reflecting an enduring adaptive response to extreme nutritional deprivation (19).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Abstract
What the sources say
- Supportedcites [19] Yehuda, 2009, Enduring effects of severe developmental adversity, including nutritional deprivation, on cortisol metabolism in aging Holocaust survivors, J Psychiatr Res source
The Results report a significantly elevated urinary F/E ratio in Holocaust survivors compared with controls, suggesting lower 11β-HSD-2 activity. The Discussion describes this change as potentially beneficial during starvation or salt depletion and associates it with starvation or other Holocaust-specific trauma, consistent with the claim’s hedged interpretation. (LLM, conf=0.91)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“FKBP5 effectively decreases glucocorticoid binding to GR, impeding GR translocation to the nucleus (29,30).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Not checked — no full text of the sourcecites [29] Pratt, 1997, Steroid receptor interactions with heat shock protein and immunophilin chaperones, Endocr Rev source
- Partly supportedcites [30] Wochnik, 2005, FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells, J Biol Chem sourceExperimental — accuracy not yet measured
The Discussion reports reduced hormone binding and demonstrates that FKBP51 delays GR nuclear translocation. But it describes impaired translocation as an additional effect: the 'FKBP51 Inhibits Nuclear Translocation of GR' section finds a delay even at saturating hormone concentrations, when the binding-affinity effect is excluded. The claim's implication that reduced binding causes the translocation delay is therefore too broad. (LLM, conf=0.83)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Early abuse induced demethylation in the presence of the FKBP5 risk allele was demonstrated for three of the sites (3 to 5) in adult peripheral blood (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results report that, in DNA from peripheral blood cells, three CpGs in FKBP5 intron 7 showed an average 12.3% decrease in methylation among childhood-abuse-exposed risk-allele carriers compared with the other groups. The Methods identify peripheral blood as the DNA source. (LLM, conf=0.91)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring (10-13), but blood samples will not permit ascertainment of gamete-dependent transmission.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > DISCUSSION
What the sources say
- Supportedcites [10] Dias, 2014, Parental olfactory experience influences behavior and neural structure in subsequent generations, Nat Neurosci source
The Results section says the authors investigated sperm for epigenetic changes because their data suggested inheritance via parental gametes; they found reduced methylation at an olfactory-receptor locus in sperm from exposed fathers. This supports the cited proposition that gamete-based epigenetic effects are a potential explanation for effects in offspring. The statement about what blood samples can establish follows the citation and is not attributed to this source. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [11] Zaidan, 2013, Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring, Biol Psychiatry source
- Supportedcites [12] Franklin, 2010, Epigenetic transmission of the impact of early stress across generations, Biol Psychiatry source
The citation attaches to the proposed gamete-based explanation, not the subsequent statement about blood samples. The Results report altered DNA methylation in the male germline that may be passed to offspring, supporting a paternal-gamete mechanism; the paper need not establish a maternal mechanism to support this possibility. (LLM, conf=0.91)
- Supportedcites [13] Rodgers, 2013, Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation, J Neurosci source
The Introduction (page not provided) proposes epigenetic marks in germ cells as a mechanism by which parental exposures affect offspring, while discussing both maternal and paternal studies. The citation is attached to that proposed gamete-dependent mechanism; the statement about what blood samples can establish is the citing authors’ uncited qualification. (LLM, conf=0.91)
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“FKBP5 single nucleotide polymorphisms have additionally been shown to interact with early trauma to predict both PTSD and major depression (36,37), possibly through involvement of allelespecific, environmentally dependent changes in methylation of specific cytosine-phosphate-guanine (CpG) sites (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Partly supportedcites [36] Binder, 2008, Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults, JAMA sourceExperimental — accuracy not yet measured
The COMMENT reports that FKBP5 SNPs interacted with child abuse to predict adult PTSD symptoms. The “FKBP5 and Child Abuse Interaction” section reports no significant genotype-by-child-abuse interaction for depression outcome after correction for multiple testing. This source therefore supports the PTSD part, but not the claim about major depression. (LLM, conf=0.90)
- Partly supportedcites [37] Koenen, 2010, FKBP5 polymorphisms modify the effects of childhood trauma, Neuropsychopharmacology sourceExperimental — accuracy not yet measured
The main text reports that FKBP5 SNP rs9470080 interacted with childhood adversity to predict PTSD risk in African-American participants; the interaction was not significant in European Americans. It does not report an FKBP5–early-trauma interaction predicting major depression. The depression study listed in the References concerns CRHR1, not FKBP5. (LLM, conf=0.87)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“alterations of which have been associated with both PTSD and intergenerational effects (27,28).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Could not verifycites [27] Lehrner, 2014, Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors, Psychoneuroendocrinology sourceExperimental — accuracy not yet measured
The Results report an association between maternal PTSD and offspring glucocorticoid sensitivity, and the Discussion considers possible intergenerational mechanisms. Neither section identifies FKBP5 or links alterations of it to PTSD or intergenerational effects (searched: FKBP5 and FK506-binding protein 5). (LLM, conf=0.72)
- Not checked — no full text of the sourcecites [28] Daskalakis, 2013, Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment, Endocrinol Metab Clin North Am source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Intron 7 sites are located within, or in proximity to, functional consensus glucocorticoid response elements (GREs) and are demethylated by glucocorticoids, particularly during developmentally sensitive periods (38).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Supportedcites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Methods (page not supplied) locate the intron 7 CpG sites within or near consensus GREs. The Results (page not supplied) report dexamethasone-induced demethylation of those sites and a sensitive period during which glucocorticoid exposure produced the effect. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“FKBP5 gene expression has been shown to be altered in PTSD and major depression (32)(33)(34)(35).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Supportedcites [32] Menke, 2013, Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression, Genes Brain Behav source
The Abstract (page unavailable) reports genotype-specific gene-expression changes in PTSD. The Stimulated FKBP5 mRNA expression section (page unavailable) reports a significant difference in FKBP5 mRNA induction between depressed patients and controls carrying the same risk allele. Together, these passages support the broad claim that FKBP5 expression is altered in both conditions. (LLM, conf=0.88)
- Partly supportedcites [33] Mehta, 2011, Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: Evidence from endocrine and gene expression studies, Arch Gen Psychiatry sourceExperimental — accuracy not yet measured
The Results and Comment sections report genotype-dependent changes in FKBP5 expression associated with PTSD symptoms, including a replicated association. The passages do not report altered FKBP5 expression in major depression, so this source supports only the PTSD part of the claim. Page numbers were not provided in our copy. (LLM, conf=0.88)
- Partly supportedcites [34] Sarapas, 2011, Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks, Dis Markers sourceExperimental — accuracy not yet measured
The genetic analysis (§3.3; page unavailable) links lower FKBP5 expression to greater PTSD symptom severity. The Discussion (§4; page unavailable) does not establish altered FKBP5 gene expression in major depression: it reports that a depression-associated genotype was not related to FKBP5 mRNA expression, although it was associated with higher protein levels. (LLM, conf=0.88)
- Supportedcites [35] Yehuda, 2009, Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks, Biol Psychiatry source
The Results report significantly decreased FKBP5 expression in participants with PTSD. The Discussion also reports that FKBP5 expression in recurrent depression was altered in the opposite direction; the paper does not present that depression finding as its own experiment. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Indeed, for the NR3C1 gene, associations of individual sites with exposures to several types of adversity are increasingly recognized (52).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Supportedcites [52] Daskalakis, 2014, Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic review of contributing factors, Front Neurosci source
The GR-1F promoter site-specific methylation section reviews site-specific NR3C1 methylation findings across 16 studies. It identifies associations with several forms of adversity, including prenatal maternal mood, childhood abuse, parental loss, and other early stressful events. The supplied passages do not provide page numbers. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The main finding in this study is that Holocaust survivors and their offspring have methylation changes on the same site in a functional intronic region of the FKBP5 gene, a GR-binding sequence in intron 7, but in the opposite direction.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither parental PTSD (β 5 .134,ns) nor the presence of the FKBP5 risk allele (β 5 2.044, ns) contributed to the model.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > FKBP5 Intron 7 Methylation Holocaust Offspring and F1 Comparison Subjects
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, like the CTQ total score, emotional abuse was not significantly associated with bin 3/site 6 methylation (β 5 .018,ns) and did not alter the significance of Holocaust exposure at this site (β 5 2.375, p 5 .045).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > FKBP5 Intron 7 Methylation Holocaust Offspring and F1 Comparison Subjects
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Adding childhood adversity as measured by the CTQ total score did not alter the predictive significance of parental exposure (β 5 2.359, p 5 .049)and was not a predictor of bin 3/site 6 methylation (β 5 2.034, ns).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > FKBP5 Intron 7 Methylation Holocaust Offspring and F1 Comparison Subjects
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mechanism of intergenerational transmission of epigenetic effects at bin 3/site 6 is not known but does not appear to be mediated by childhood adversity, as is the case for bin 2.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Biological Psychiatry
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast to the findings at bin 3/site 6, which relate to parental exposure, bin 2/sites 3 to 5 methylation was associated with offspring trauma exposure (childhood physical and sexual abuse), but the direction depended on the presence of the FKBP5 risk allele.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It should be noted that mean CTQ subscale and total scores for the Holocaust offspring were generally lower than reported in other population samples”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Parental trauma exposure is associated with greater risk for posttraumatic stress disorder (PTSD) and mood and anxiety disorders in offspring (1,2).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Yehuda, 1998, Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors, Am J Psychiatry source
- Not checked — no full text of the sourcecites [2] Weissman, 2005, Families at high and low risk for depression: A 3-generation study, Arch Gen Psychiatry source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The finding was unchanged without covariation (F 1,29 5 4.91, p 5 .035)and when presence of lifetime PTSD in offspring (p 5 .036)or severity of childhood trauma (p 5 .049)were added, respectively, as additional covariates.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > FKBP5 Intron 7 Methylation Holocaust Offspring and F1 Comparison Subjects
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bin 3/site 6 methylation was not associated with the FKBP5 risk allele and could not be attributed to the offspring's own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > DISCUSSION
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“in the aforementioned study, the increase in offspring 11β-HSD-2 activity was interpreted as a protective adaptation to mitigate exposure to elevated maternal glucocorticoids associated with reduced maternal 11β-HSD-2 activity (20,50).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Not checked — no full text of the sourcecites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source
- Not checked — no full text of the sourcecites [50] Yehuda, 2011, Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis, Endocrinology source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The addition of presence/absence of the FKBP5 risk allele as a covariate did not appreciably alter the finding (p 5 .053),suggesting that bin 3/site 6 methylation changes in F0 were driven more by exposure than genetic variation in this single nucleotide polymorphism.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > FKBP5 Intron 7 Methylation in Holocaust Survivors and F0 Comparison Subjects
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“We previously reported a directional difference between parents and offspring in 11β-HSD-2 activity, which was interpreted as an accommodation in the offspring during a sensitive developmental window to the biological consequences of parental trauma exposure (20).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Not checked — no full text of the sourcecites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Like FKBP5, 11β-HSD-2 is a moderator of glucocorticoid action”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The directional difference in bin 3/site 6 methylation between Holocaust survivors and their offspring was unexpected but may reflect an intergenerational biological accommodation.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In turn, FKBP5 gene expression is regulated by GR binding, forming an intracellular ultrashort glucocorticoid negative-feedback loop that regulates FKBP5 and GR (26,31).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > SEE COMMENTARY ON PAGE
What the sources say
- Not checked — no full text of the sourcecites [26] Binder, 2009, The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders, Psychoneuroendocrinology source
- Not checked — no full text of the sourcecites [31] Jaaskelainen, 2011, Steroid up-regulation of FKBP51 and its role in hormone signaling, Curr Opin Pharmacol source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant differences between the groups in age, gender, years of education, current anxiety or mood disorder diagnoses, or frequency of the FKBP5 risk allele.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Survivor and Comparison Group Demographic Characteristics
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant differences between the groups in age, gender, years of education, childhood trauma scores, psychiatric diagnoses, frequency of the FKBP5 risk allele, or cortisol levels.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Offspring and Comparison Group Demographic Characteristics
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the effect was reduced when controlling for parental PTSD (F 1,23 5 2.59, p 5 .121),suggesting an influence of parental PTSD symptoms.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > FKBP5 Intron 7 Methylation Holocaust Offspring and F1 Comparison Subjects
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Genotypes of rs1360780 were in Hardy-Weinberg equilibrium (p ..05).”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Genotyping.
Strength:plain· not yet calibratedn = 71Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In addition, even within the same cell type, observed global changes reflect diverse changes in single cells, as has been reported in a number of articles using clone-based sequencing for methylation analysis [for example (16,17,54)].”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Holocaust Exposure and Intergenerational FKBP5 Methylation
What the sources say
- Not checked — no full text of the sourcecites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
- Not checked — no full text of the sourcecites [17] Murgatroyd, 2009, Dynamic DNA methylation programs persistent adverse effects of early-life stress, Nat Neurosci source
- Not checked — no full text of the sourcecites [54] Yehuda, 2015, Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder, Biol Psychiatry source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All F1 participants were raised by their biological parents.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > METHODS AND MATERIALS Sample
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The intra-assay and interassay coefficients of variation were 2.3% and 6.1%, respectively.”
§ Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation > Hormone Measurement.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
A major gap in the clinical literature is that parents and their adult offspring have not been studied in tandem, making it difficult to understand the origin of changes in association with parental exposure.
“A major gap in the clinical literature is that parents and their adult offspring have not been studied in tandem, making it difficult to understand the origin of changes in association with parental exposure.”
The paper relies on this without support.
What can be detected in blood samples is parental and offspring experience-dependent epigenetic modifications.
“What can be detected in blood samples is parental and offspring experience-dependent epigenetic modifications.”
The paper relies on this without support.
The observed associations between parental Holocaust exposure and offspring FKBP5 methylation reflect intergenerational transmission of epigenetic effects rather than preconception or postnatal influences or offspring recalibration of glucocorticoid regulation.
“At present, it is not clear whether glucocorticoid programming in offspring reflects intergenerational consequences of parental exposure or offspring recalibration of glucocorticoid regulation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD (e.g., Yehuda et al., 2016;Methal et al., 2019).”
From DNA methylation of NR3C1 and FKBP5 is associated with posttraumatic stress disorder, posttraumatic growth, and resilience. (2020) · cites this paper as Yehuda et al., 2016
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Across survivor populations and their descendants, research suggests coordinated involvement of stress-response regulation, neurodevelopmental signaling, and behavioral adaptation (7, 82–100).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies of Holocaust survivors and their offspring demonstrate differential DNA methylation of key HPA-axis genes, including NR3C1 and FKBP5, corresponding with variation in glucocorticoid receptor sensitivity and cortisol feedback regulation (82, 83).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Variation in FKBP5 methylation across intronic regions has also been reported, with opposite directional patterns observed in survivors and their offspring, corresponding with differences in FKBP5 expression and glucocorticoid receptor sensitivity (83, 84).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“FKBP5 methylation differences have been reported across multiple trauma contexts in both survivors and offspring, raising the possibility that stress-response regulatory genes may help distinguish individuals more likely to benefit from specific interventions (38, 66, 83, 84, 136).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A substantial proportion of studies have focused on a limited number of stress-response genes, most notably FKBP5 and NR3C1 (55, 65, 83, 84, 121, 129).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For example, a preliminary study examining FKBP5 intron 7 methylation in Holocaust survivors and their children demonstrated alterations at the same site within intron 7 in both parents and their children, with no specific consideration of parental gender or PTSD 127 .”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [127]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In 32 Holocaust survivors and their 22 adult offspring compared to eight non-exposed control parents and their nine children, parental Holocaust exposure was found to predict FKBP5 intron 7 methylation in offspring.”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Yehuda et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Methylation of the third GRE in intron 7 was further positively correlated with methylation at the same site in their offspring and overall average methylation of intron 7 was negatively correlated with wake-up cortisol”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Yehuda et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, offspring carrying the FKBP5 rs1360780 A risk allele showed a significant negative correlation between the degree of physical and sexual childhood abuse and CpG methylation across the first GRE in intron 7, while G/G genotype carriers displayed a positive correlation”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Yehuda et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Of note, increased whole blood CpG methylation was observed in the third (of a total of three) GRE of FKBP5 intron 7 in Holocaust survivors compared to contemporary Jewish controls, while children of Holocaust survivors were characterized by decreased methylation compared to control children”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Yehuda et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Potential epigenetic effects in maternal or paternal gametes could not, however, be investigated.”
The cited source says what the claim attributes to it.
In the citing paper
“Exposed parents had an average of 10% higher methylation compared to unexposed, while exposed offspring had 7.7% lower methylation.”
The cited source says what the claim attributes to it.
In the citing paper
“In their analysis, Yehuda and colleagues also controlled for current PTSD (51.6% of the Holocaust-exposed parents), childhood trauma in the offspring, or genetic variation in the gene.”
The cited source says what the claim attributes to it.
In the citing paper
“Holocaust exposure was associated with blood DNA methylation of the FKBP5 gene at the same transcriptionally active site in both generations, although interestingly in opposing directions.”
The cited source says what the claim attributes to it.
In the citing paper
“The majority of the studies looked at only maternal transmission, but four considered both maternal and paternal [83,94,95,102], and two focused only on fathers [97,104].”
The cited source says what the claim attributes to it.
In the citing paper
“Of the five studies that measured FKBP5 DNA methylation, three found lower methylation in the offspring of exposed parents [83,94,99], one found an opposite association with higher methylation [103], and another reported no association [88].”
The cited source says what the claim attributes to it.
In the citing paper
“There were six studies of trauma or PTSD following war, including two studies of Holocaust survivors [83,94,95], two studies on the Rwandan genocide [90,91], and one each from the Kosovo War [96] and Vietnam veterans [97].”
The cited source says what the claim attributes to it.
In the citing paper
“However, interestingly, they were directionally distinct (when compared to their respective control groups), with Holocaust offspring showing lower methylation at this site compared to demographically-matched controls, and Holocaust survivors demonstrating higher methylation compared to respective controls.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [127]
The cited source says what the claim attributes to it.
In the citing paper
“FKBP5 methylation in parents and their children were positively correlated.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [127]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“While hypothesis-driven candidate gene studies can provide mechanistic insight, narrow locus selection risks overemphasizing the importance of specific genes while overlooking broader regulatory networks (83, 84, 121, 129).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
Experimental — accuracy not yet measuredIn the citing paper
“Multiple human studies have indicated that traumas such as combat exposure, forced displacement, genocide exposure, and low maternal bonding may be passed on inter-generationally, and have been associated with both psychopathology in children and DNA methylation in the FKBP5 gene.45,46”
From The role of epigenetics in psychological resilience (2021) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Control offspring trauma total does not match its subscales
MinorThe five listed mean trauma subscale scores for comparison offspring sum to 35.6, not the reported total mean of 30.2. The gap exceeds what rounding the subscale means could explain.
Reported 30.2 · recomputed 35.6
“| Total score | 36.7 6 11.5 | 30.2 6 6.9 | F 1,30 5 2.46, ns |”
Emotional-abuse direction conflicts with the table
MinorThe discussion of this sample implies greater emotional abuse among Holocaust offspring, whereas Table 2 lists a lower mean for them than for comparison offspring.
“Since emotional abuse is reported substantially more often by Holocaust survivor offspring (25) and was reported in this sample at a trend level of significance (t 5 21.98, df 5 24.89, p 5 .059),we tested emotional abuse in the regression model.”
“| Emotional abuse | 9.0 6 5.4 | 12.0 6 3.3 | F 1,30 5 2.57, ns |”
A predictor is called significant at p = .054
MinorThe paper sets significance at p < .05 but describes parental exposure as remaining significant in a model where its reported p-value is .054.
“In each of these, however, parental exposure remained a significant predictor (respectively, β 5 2.461, p 5 .054;β 5 2.362, p 5 .043).”
“Finally, statistical significance for all analyses was set at two-tailed, p , .05.”
Offspring anxiety diagnosis differs significantly in the table
MinorThe text says psychiatric diagnoses did not differ between offspring groups, but Table 2 reports a significant difference for current anxiety disorder.
“There were no significant differences between the groups in age, gender, years of education, childhood trauma scores, psychiatric diagnoses, frequency of the FKBP5 risk allele, or cortisol levels.”
“| Current Anxiety Disorder (except PTSD) d | 8 (36.4%) | 0 (0%) | χ 2 1 5 6.56, p 5 .041 |”
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Self-citation
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Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms
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“For instance, Holocaust survivors exhibited inverse 11β-HSD2 activity and FKBP5 methylation compared with their offspring (Yehuda et al, 2009; Bierer et al, 2014; Yehuda et al, 2015).”
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“Most notably a study on the offspring of Holocaust survivors identified altered methylation status of the gene encoding FK506 binding protein, a regulator of glucocorticoid receptor sensitivity, in blood (54).”
BackgroundNeurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders
Notaras, M. J., & van den Buuse, M. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0639-2 · Cited by 404
Zannas, A. S., Jia, M., Hafner, K., Baumert, J., Wiechmann, T., Pape, J. C., Arloth, J., Ködel, M., Martinelli, S., Roitman, M., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816847116 · Cited by 351
Self-citationBiological embedding of experience: a primer on epigenetics
Aristizabal, M. J., Anreiter, I., Halldorsdottir, T., Odgers, C. L., McDade, T. W., Goldenberg, A., Mostafavi, S., Kobor, M. S., Binder, E. B., Sokolowski, M. B., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820838116 · Cited by 268
Self-citationParental Advisory: Maternal and Paternal Stress Can Impact Offspring Neurodevelopment
Chan, J. C., Nugent, B. M., & Bale, T. L. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.005 · Cited by 241
“Studies in children whose mothers survived the Holocaust suggest that one mechanism whereby maternal preconception stress may affect future generations is via alterations in DNA methylation of stress regulatory genes, such as FKBP5 and GR, which results in enhanced HPA stress axis sensitivity (73,74).”
BackgroundThe hypothalamic-pituitary-adrenal axis in PTSD: Pathophysiology and treatment interventions
Dunlop, B. W., & Wong, A. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.10.010 · Cited by 271
Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders
Schiele, M. A., & Domschke, K. (2018) · Genes, Brain and Behavior · doi:10.1111/gbb.12423 · Cited by 233
Matosin, N., Halldorsdottir, T., & Binder, E. B. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.01.021 · Cited by 226
Self-citationPrenatal stress and epigenetics
Cao-Lei, L., de Rooij, S. R., King, S., Matthews, S. G., Metz, G. A. S., Roseboom, T. J., & Szyf, M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.016 · Cited by 253
Dashorst, P., Mooren, T. M., Kleber, R. J., de Jong, P. J., & Huntjens, R. J. C. (2019) · European Journal of Psychotraumatology · doi:10.1080/20008198.2019.1654065 · Cited by 207
“The study by Yehuda et al. (2016) demonstrated methylation changes (large effect sizes) at the FKBP-5 gene, in the opposite direction, survivors had significantly higher and HSO significantly lower methylation.”
BackgroundInfluentialNindl, B. C., Billing, D. C., Drain, J. R., Beckner, M. E., Greeves, J. P., Groeller, H., Teien, H. K., Marcora, S., Moffitt, A., Reilly, T. J., et al. (2018) · Journal of science and medicine in sport · doi:10.1016/j.jsams.2018.05.005 · Cited by 195
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Stress, female reproduction and pregnancy
Valsamakis, G., Chrousos, G. P., & Mastorakos, G. P. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.09.031 · Cited by 198
Marzi, S. J., Sugden, K., Arseneault, L., Belsky, D. W., Burrage, J., Corcoran, D. L., Danese, A., Fisher, H. L., Hannon, E., Moffitt, T. E., et al. (2018) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2017.17060693 · Cited by 163
“Under the label of “adversity,” studies have focused on a diverse mix of exposures spanning maternal psychiatric disease (13), early parental loss (14), institutionalization (15), indentured child labor (16), child abuse (17), and the Holocaust (18).”
BackgroundMy grandmother’s hands: racialized trauma and the pathway to mending our hearts and bodies
Jehangir, A. (2021) · Social Work Education · doi:10.1080/02615479.2021.1976760 · Cited by 169
Epigenetic programming by stress and glucocorticoids along the human lifespan
Zannas, A. S., & Chrousos, G. P. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.35 · Cited by 158
Schiele, M. A., Gottschalk, M. G., & Domschke, K. (2020) · Clinical Psychology Review · doi:10.1016/j.cpr.2020.101830 · Cited by 156
Losing DNA methylation at repetitive elements and breaking bad
Pappalardo, X. G., & Barra, V. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00400-z · Cited by 165
Post‐traumatic stress disorder and beyond: an overview of rodent stress models
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Paternal grandfather’s access to food predicts all-cause and cancer mortality in grandsons
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Recent Genetics and Epigenetics Approaches to PTSD
Daskalakis, N. P., Rijal, C. M., King, C. D., Huckins, L. M., & Ressler, K. J. (2018) · Current Psychiatry Reports · doi:10.1007/s11920-018-0898-7 · Cited by 152
Self-citationThe epigenetic impacts of social stress: how does social adversity become biologically embedded?
Cunliffe, V. T. (2016) · Epigenomics · doi:10.2217/epi-2016-0075 · Cited by 141
The Role of Mindfulness in Reducing the Adverse Effects of Childhood Stress and Trauma
Ortiz, R., & Sibinga, E. M. S. (2017) · Children · doi:10.3390/children4030016 · Cited by 165
“Remarkably, such epigenetic modifications may carry across generations, as identified in the glucocorticoid receptor related gene FKBP5 of holocaust survivors also found in their offspring [15].”
BackgroundTransgenerational epigenetics of traumatic stress
Jawaid, A., Roszkowski, M., & Mansuy, I. M. (2018) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2018.03.003 · Cited by 134
Barker, E. D., Walton, E., & Cecil, C. A. M. (2018) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12782 · Cited by 134
“received considerable theoretical interest, and recent research suggests this possibility (Yehuda et al., 2016).”
Scorza, P., Duarte, C. S., Hipwell, A. E., Posner, J. E., Ortin‐Peralta, A., CANINO, G. J., Monk, C. E., & Outcomes, P. C. F. E. I. O. C. H. (2018) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12877 · Cited by 144
Pluripotent stem cells in neuropsychiatric disorders
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Trauma across generations and paths to adaptation and resilience
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“[17] study, the DNA methylation seen in the offspring was noted to be opposite from that seen in their parents.”
BackgroundGassen, N. C., Chrousos, G. P., Binder, E. B., & Zannas, A. S. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.003 · Cited by 131
“Furthermore, studies in human cohorts show that life stressrs, especially early in development, can induce lasting changes in NA methylation, both at specific candidate loci as well as on a enome-wide level (Boks et al., 2015; Brody et al., 2016a, 2016b; lengel et al., 2013; McGowan et al., 2009; Non et al., 2014; Per…”
BackgroundSelf-citationCultural trauma as a fundamental cause of health disparities
Subica, A. M., & Link, B. G. (2022) · Social Science & Medicine · doi:10.1016/j.socscimed.2021.114574 · Cited by 123
“, depression, metabolic syndrome, cardiovascular disease)(Bierer et al., 2014; Darity et al., 2001; Heckman and Payner, 1989; Yehuda et al., 2016).”
Tyrka, A. R., Ridout, K. K., & Parade, S. H. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000870 · Cited by 119
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Glucocorticoids as Mediators of Adverse Outcomes of Prenatal Stress
Krontira, A. C., Cruceanu, C., & Binder, E. B. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.03.008 · Cited by 124
Self-citationMatheson, K., Foster, M. D., Bombay, A., McQuaid, R. J., & Anisman, H. (2019) · The International Journal of Ecopsychology (IJE) · doi:10.3389/fpsyg.2019.00416 · Cited by 138
“For example, religious beliefs might enable individuals to find meaning in their traumatic experiences (God’s will) and thereby protect against the negative effects on mental health (Ysseldyk et al., 2011).”
The role of epigenetics in psychological resilience
Smeeth, D., Beck, S., Karam, E. G., & Pluess, M. (2021) · The Lancet Psychiatry · doi:10.1016/s2215-0366(20)30515-0 · Cited by 108
Non, A. L., Hollister, B. M., Humphreys, K. L., Childebayeva, A., Esteves, K. C., Zeanah, C. H., Fox, N. A., Nelson, C. A., & Drury, S. S. (2016) · American Journal of Physical Anthropology · doi:10.1002/ajpa.23010 · Cited by 114
“In contrast, increased DNA methylation at intron 7 has been observed at multiple CpG sites in FKBP5 in Holocaust survivors, although lower methylation was observed in their offspring, suggesting an inter-generational biological accommodation of trauma at this gene (Yehuda et al., 2015).”
BackgroundEpigenetics as a Driver of Developmental Origins of Health and Disease: Did We Forget the Fathers?
Soubry, A. (2017) · BioEssays · doi:10.1002/bies.201700113 · Cited by 114
“Yehuda et al., 2016[73] Retrospective cohort 31 Holocaust offspring, 9 Jewish US citizens (demographically matched) USA Feinberg et al., 2015[93] Cohort 44 fathers with at least one autistic child 4 sites, US Northstone et al., 2014[62] Birth cohort 9886 fathers Avon, UK Soubry et al., 2013[65]…”
BackgroundDaskalakis, N. P., Cohen, H., Nievergelt, C. M., Baker, D. G., Buxbaum, J. D., Russo, S. J., & Yehuda, R. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.07.024 · Cited by 105
Self-citationGlucocorticoid receptor DNA methylation, childhood maltreatment and major depression
Bustamante, A. C., Aiello, A. E., Galea, S., Ratanatharathorn, A., Noronha, C., Wildman, D. E., & Uddin, M. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.07.038 · Cited by 104
“Similar binning approaches have been applied to analyses of stress-related effects on other HPA axis genes, in which functionally distinct regions are grouped together in bins (e.g. FKBP5; (Klengel et al., 2013; Yehuda et al., 2015).”
MethodIntergenerational transmission of DNA methylation signatures associated with early life stress
Stenz, L., Schechter, D. S., Serpa, S. R., & Paoloni-Giacobino, A. (2018) · Current Genomics · doi:10.2174/1389202919666171229145656 · Cited by 101
“Interestingly, FKBP5 has been reported to interact with NR3C1 as a co-chaperone of the glucocorticoid receptor complex [82].”
BackgroundGlucocorticoids and Hippocampal Structure and Function in PTSD
Szeszko, P. R., Lehrner, A. L., & Yehuda, R. (2018) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000188 · Cited by 112
Self-citationAbnormal Epigenetic Regulation of Immune System during Aging
Jasiulionis, M. G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00197 · Cited by 103
Intergenerational Mobility and Equality of Opportunity
Torche, F. (2015) · European Journal of Sociology · doi:10.1017/s0003975615000181 · Cited by 100
Impact of Parental Exposure on Offspring Health in Humans
Jawaid, A., Jehle, K.-L., & Mansuy, I. M. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.10.006 · Cited by 110
Plasticity of the epigenome during early-life stress
Barnett-Burns, S., Szyszkowicz, J. K., Luheshi, G. N., Lutz, P.-É., & Turecki, G. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.09.033 · Cited by 97
Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives
Hertel, J., König, J., Homuth, G., der Auwera, S. V., Wittfeld, K., Pietzner, M., Kacprowski, T., Pfeiffer, L., Kretschmer, A., Waldenberger, M., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-13927-7 · Cited by 99
Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus
Wiechmann, T., Röh, S., Sauer, S., Czamara, D., Arloth, J., Ködel, M., Beintner, M., Knop, L., Menke, A., Binder, E. B., et al. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0682-5 · Cited by 81
Self-citationA review of epigenetic contributions to post-traumatic stress disorder
Howie, J. H., Rijal, C. M., & Ressler, K. J. (2019) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2019.21.4/kressler · Cited by 103
Intergenerational Effects of Maternal Holocaust Exposure on FKBP5 Methylation
Bierer, L. M., Bader, H. N., Daskalakis, N. P., Lehrner, A., Provençal, N., Wiechmann, T., Klengel, T., Makotkine, I., Binder, E. B., & Yehuda, R. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19060618 · Cited by 86
Self-citationRyan, J., Chaudieu, I., Ancelin, M.-L., & Saffery, R. (2016) · Epigenomics · doi:10.2217/epi-2016-0083 · Cited by 85
Genetics of glucocorticoid regulation and posttraumatic stress disorder -what do we know?
Castro-Vale, I., van Rossum, E. F. C., Machado, J. C., Mota-Cardoso, R., & Carvalho, D. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.005 · Cited by 85
Epigenetic legacy of parental experiences: Dynamic and interactive pathways to inheritance
Champagne, F. A. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000808 · Cited by 81
“The persistence across generations of the effects of parental experiences has been demonstrated in humans in studies of famine and trauma exposure (Kaati, Bygren, Pembrey, & Sjostrom, 2007; Yehuda et al., 2015) and may contribute to the observed familial transmission of psychopathology (Oquendo et al.”
BackgroundMorris, G., Berk, M., Maes, M. H. J., Carvalho, A. F., & Puri, B. K. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1498-1 · Cited by 91
Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders
Mourtzi, N., Sertedaki, A., & Charmandari, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115964 · Cited by 95
Understanding the epigenetic basis of sex differences in depression
Hodes, G. E., Walker, D. M., Labonté, B., Nestler, E. J., & Russo, S. J. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23876 · Cited by 87
“The concept that the experience of stress in one individual can lead to altered stress sensitivity in its offspring is relatively new but has gained substantial traction in recent years (Yuan et al., 2015).”
BackgroundMatosin, N., Cruceanu, C., & Binder, E. B. (2017) · Chronic Stress · doi:10.1177/2470547017710764 · Cited by 92
“Even from the first possible window of stress exposure—in utero—organisms may be susceptible to epigenetic programming which persists into adult life (Table 1(a)).80 In particular, epigenetic differences in key genes that regulate the HPA axis are reported in people exposed to prenatal adversity.80 These effects are h…”
BackgroundSelf-citationThe role of DNA methylation in the pathophysiology and treatment of bipolar disorder
Fries, G. R., Li, Q., McAlpin, B. R., Rein, T., Walss‐Bass, C., Soares, J. C., & Quevedo, J. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.010 · Cited by 85
“…measure the so-called ‘non genetic intergenerational transmission’ of DNA methylation patterns over generations (Weber-Stadlbauer et al., 2016; Yehuda et al., 2015), which will in fact demonstrate whether the risk shown by populations at familial risk of BD can be modulated by such…”
BackgroundEarly Environments, Stress, and the Epigenetics of Human Health
Mulligan, C. J. (2016) · Annual Review of Anthropology · doi:10.1146/annurev-anthro-102215-095954 · Cited by 82
“…disorders in adulthood (Klengel et al. 2013), with Holocaust survivors and their offspring, with some cases of childhood physical and sexual abuse (Yehuda et al. 2015), with low socioeconomic status (SES) during childhood (Needham et al. 2015), and with severe social deprivation, such as…”
Matheson, K., Seymour, A. M., Landry, J., Ventura, K., Arsenault, E., & Anisman, H. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19116455 · Cited by 111
“These behavioral and hormonal alterations were, in many instances, accompanied by epigenetic changes in both the survivors and their children [145], varying in relation to whether one or both parents had been survivors, as well as whether one or both parents had developed PTSD [146].”
BackgroundKlinger-König, J., Hertel, J., Van der Auwera, S., Frenzel, S., Pfeiffer, L., Waldenberger, M., Golchert, J., Teumer, A., Nauck, M., Homuth, G., et al. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0319-6 · Cited by 78
Karanikas, E., Daskalakis, N. P., & Agorastos, A. (2021) · Brain Sciences · doi:10.3390/brainsci11060723 · Cited by 78
Self-citationGenomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD
Mehta, D., Bruenig, D., Carrillo‐Roa, T., Lawford, B., Harvey, W., Morris, C. P., Smith, A. K., Binder, E. B., Young, R. M., & Voisey, J. (2017) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12778 · Cited by 78
“including transgenerational inheritance of DNA methylation marks (71).”
BackgroundSelf-citationTransgenerational epigenetic inheritance: from phenomena to molecular mechanisms
Liberman, N., Wang, S. Y., & Greer, E. L. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.09.012 · Cited by 79
“famine during the Dutch Hunger Winter was associated with lower cytosine methylation on the imprinted insulinlike growth factor 2 (IGF2) gene [85] and decreased cytosine methylation in the FKBP5 (FK506 Binding Protein 5) gene was correlated with stress levels in the offspring of Holocaust survivors [29].”
BackgroundSchuebel, K., Gitik, M., Domschke, K., & Goldman, D. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw058 · Cited by 75
How to Forget the Unforgettable? On Collective Trauma, Cultural Identity, and Mnemotechnologies
Aydin, C. (2017) · Identity · doi:10.1080/15283488.2017.1340160 · Cited by 83
“Recently, Yehuda et al. (2015) indicated that children of genocide survivors can even inherit trauma in their DNA.”
BackgroundEpigenetics of prenatal stress in humans: the current research landscape
Dieckmann, L., & Czamara, D. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01635-9 · Cited by 92
“DNAm changes in FKBP5 were also reported in blood samples of adult offspring of holocaust survivors [106].”
BackgroundHow are social determinants of health integrated into epigenetic research? A systematic review
Evans, L. A., Engelman, M., Mikulas, A., & Malecki, K. M. C. (2021) · Social Science & Medicine · doi:10.1016/j.socscimed.2021.113738 · Cited by 73
“For example, one study examined state-sponsored persecution inflicted upon Jewish Holocaust survivors and intergenerational trauma carried forward to adult offspring (Yehuda et al., 2016) and another investigated direct exposure to the Rwandan Evans et al.”
BackgroundSuchdev, P. S., Boivin, M. J., Forsyth, B. W. C., Georgieff, M., Guerrant, R. L., & Nelson, C. A. (2017) · PEDIATRICS · doi:10.1542/peds.2016-2828e · Cited by 73
Nöthling, J., Malan-Müller, S., Abrahams, N., Hemmings, S. M. J., & Seedat, S. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2019.1583369 · Cited by 74
Neuroscience of trauma and the Russian invasion of Ukraine
Jawaid, A., Gomółka, M., & Timmer, A. (2022) · Nature Human Behaviour · doi:10.1038/s41562-022-01344-4 · Cited by 70
Ramo-Fernández, L., Boeck, C., Koenig, A. M., Schury, K., Binder, E. B., Gündel, H., Fegert, J. M., Karabatsiakis, A., & Kolassa, I.-T. (2019) · Scientific Reports · doi:10.1038/s41598-018-36689-2 · Cited by 67
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A Review of Psychological Stress among Students and Its Assessment Using Salivary Biomarkers
Špiljak, B., Vilibić, M., Glavina, A., Crnković, M., Šešerko, A., & Lugović‐Mihić, L. (2022) · Behavioral Sciences · doi:10.3390/bs12100400 · Cited by 85
“According to the literature, there is a correlation between blood cortisol levels and salivary cortisol values, observed particularly during stress [67].”
BackgroundBear, U. R., Thayer, Z. M., Croy, C. D., Kaufman, C. E., Manson, S. M., & the AI-SUPERPFP Team (2018) · Family & Community Health · doi:10.1097/fch.0000000000000205 · Cited by 67
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Mehta, D., Miller, O., Bruenig, D., David, G., & Shakespeare‐Finch, J. (2020) · Journal of Traumatic Stress · doi:10.1002/jts.22472 · Cited by 66
FK506 binding protein 51 integrates pathways of adaptation
Rein, T. (2016) · BioEssays · doi:10.1002/bies.201600050 · Cited by 67
“In addition, the mentioned study on Holocaust survivors and their offspring reported higher methylation of the analyzed cytosines in intron 7 of FKBP5, but lower methylation in their offspring [109].”
BackgroundInfluentialClimate change is a major stressor causing poor pregnancy outcomes and child development
Olson, D. M., & Metz, G. A. S. (2020) · F1000Research · doi:10.12688/f1000research.27157.1 · Cited by 69
In utero exposure to the Great Depression is reflected in late-life epigenetic aging signatures
Schmitz, L., & Duque, V. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2208530119 · Cited by 59
“Hunger Winter Families Study (ntreated=348) (41–43), Project Ice Storm (ntreated=34) (44–47), or research on Holocaust survivors (ntreated=54) (48), that examined the impact of maternal nutrition or stress on DNAm changes in pre-selected CpG regions that regulate specific genes.”
BackgroundPang, T. Y., Short, A. K., Bredy, T. W., & Hannan, A. J. (2017) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2017.02.007 · Cited by 61
Miller, O., Shakespeare-Finch, J., Bruenig, D., & Mehta, D. (2020) · Psychological Trauma: Theory, Research, Practice, and Policy · doi:10.1037/tra0000574 · Cited by 56
“This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD (e.g., DNA METHYLATION OF NR3C1 AND FKBP5 IS ASSOCIATED WITH TRAUMA RESPONSES 11 Yehuda et al., 2016; Methal et al., 2019).”
ResultStress Response Modulation Underlying the Psychobiology of Resilience
Averill, L. A., Averill, C. L., Kelmendi, B., Abdallah, C. G., & Southwick, S. M. (2018) · Current Psychiatry Reports · doi:10.1007/s11920-018-0887-x · Cited by 64
Zhou, A., & Ryan, J. (2023) · Genes · doi:10.3390/genes14081639 · Cited by 57
“The majority of the studies looked at only maternal transmission, but four considered both maternal and paternal [83,94,95,102], and two focused only on fathers [97,104].”
BackgroundInfluentialTherapeutic Cancer Vaccines—T Cell Responses and Epigenetic Modulation
Kartikasari, A. E. R., Prakash, M. D., Cox, M., Wilson, K., Boer, J. C., Cauchi, J. A., & Plebanski, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03109 · Cited by 54
Resilience: Safety in the Aftermath of Traumatic Stressor Experiences
Matheson, K., Asokumar, A., & Anisman, H. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.596919 · Cited by 75
“An epigenetic change of the FKBP5 gene was also apparent in their offspring; however, in this case epigenetic marks were reduced (Yehuda et al., 2016; Bierer et al., 2020).”
BackgroundBraun, K., Bock, J., Wainstock, T., Matas, E., Gaisler‐Salomon, I., Fegert, J. M., Ziegenhain, U., & Segal, M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.021 · Cited by 55
“A major development in recent years involves the realization that prenatal and preconception stress can cause long lasting epigenetic effects, mediated by DNA methylation of specific genes related to stress such as FKBP5, (Blaze and Roth, 2015; Yehuda et al., 2016).”
Psychotherapy and Genetic Neuroscience: An Emerging Dialog
Jiménez, J. P., Botto, A., Herrera, L., Leighton, C., Rossi, J. L., Quevedo, Y., Silva, J. R., Martínez, F. I., Assar, R., Salazar, L. A., et al. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00257 · Cited by 62
“Given that there is some evidence for the transgenerational transmission of epigenetic modifications in humans exposed to traumatic situations (Yehuda et al., 2016), it is possible to hypothesize that epigenetic changes produced by psychotherapy could also potentially be passed on to offspring.”
BackgroundEvidence for germline non-genetic inheritance of human phenotypes and diseases
Senaldi, L., & Smith-Raska, M. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00929-y · Cited by 61
“These findings persisted after controlling for parental post-traumatic stress disorder (PTSD) as well as a polymorphic variant associated with altered stress response; the authors conclude that parental Holocaust exposure was a significant predictor of offspring FKBP5 methylation in this group [43].”
BackgroundLiu, H., Li, T. W., Liang, L., & Hou, W. K. (2021) · Clinical Psychology Review · doi:10.1016/j.cpr.2021.102069 · Cited by 70
Environment factors, DNA methylation, and cancer
Liu, J., Huang, B., Ding, F., & Li, Y. (2023) · Environmental Geochemistry and Health · doi:10.1007/s10653-023-01749-8 · Cited by 59
“These environmental factors include poor diet [133] and living habits [163, 164], toxic chemicals [165, 166], heavy metal exposure, ionizing radiation exposure [167], psychological adversity [168, 169], and more.”
BackgroundKalyan-Masih, P., Vega-Torres, J. D., Miles, C., Haddad, E., Rainsbury, S., Baghchechi, M., Obenaus, A., & Figueroa, J. D. (2016) · eNeuro · doi:10.1523/eneuro.0125-16.2016 · Cited by 52
International Norms, Moral Psychology, and Neuroscience
Price, R. M., & Sikkink, K. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108966610 · Cited by 55
A Review of Epigenetics of PTSD in Comorbid Psychiatric Conditions
Blacker, C. J., Frye, M. A., Morava, É., Kozicz, T., & Veldić, M. (2019) · Genes · doi:10.3390/genes10020140 · Cited by 57
“A similar intergenerational transmission of epigenetic modifications in PTSD has been demonstrated in Holocaust survivors: their elevated FKBP5 (forkhead binding protein 5) methylation and their children’s decreased FKBP5 methylation were significantly different from controls [57].”
Background
Metadata
- Authors
- Yehuda, R., Daskalakis, N. P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F., & Binder, E. B.
- Affiliations
- James J. Peters VA Medical Center (US)
- Mount Sinai Hospital (US)
- Emory University (US)
- HolsboerMaschmeyer NeuroChemie (Germany) (DE)
- Corresponding author
- Yehuda, Rachel
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 80
- Issue
- 5
- Pages
- 372-380
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W1203252705
- Cited by
- 782
- References
- 60
- Citations by year
- 2026: 58 · 2025: 90 · 2024: 68 · 2023: 55 · 2022: 65 · 2021: 66 · 2020: 99 · 2019: 75 · 2018: 75 · 2017: 74 · 2016: 47
- FWCI
- 29.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- NIMH (R01 MH 64675-01)
- Biology of Risk and PTSD in Holocaust Survivor Offspring (1RC1MH088101-01)
- Mount Sinai General Clinical Research Center from the National Institute of Health (5 M01 RR00071)
- European Research Council starting (281338)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Keywords
- Holocaust survivors, intergenerational trauma, FKBP5, DNA methylation, epigenetics, glucocorticoid response element, childhood abuse, cortisol, parental trauma, site-specific methylation
- MeSH terms
- Tacrolimus Binding Protein 5, Cytosine, Female, Humans, Male, Parents, Psychiatric Status Rating Scales, Surveys and Questionnaires, Stress Disorders, Post-Traumatic, Cohort Studies, Child of Impaired Parents, Survivors, Holocaust, DNA Methylation, Tacrolimus Binding Proteins, Adult Children
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